The role of costimulation is being studied in T cell repertoire selection. Mice that are either over-expressing or deficient in costimulatory molecules B7-1 and B7-2 or the costimulatory receptor CD28 are being analyzed for expressed T cell repertoire. Studies employing T cell receptor (TCR) transgenic mice have indicated that over-expression of B7-2 can substantially affect selection of transgenic T cells in the thymus, indicating a role of costimulation in repertoire selection. Additional studies are assessing the role of CD40 and CD40L in T cell repertoire selection, and have indicated that expression of CD40L is critical to negative selection mediated by endogenous mtv gene products. The mechanism of this CD40L dependence is being investigated. Costimulatory effects are also being analyzed in the setting of tolerance to paternal antigens in pregnant mice. The effects of polymorphic self antigens on selection are also being studies using transgenic TCR and the introduction of self antigens through trans-species crosses of Mus musculus and Mus spretus mice. It has been found that self antigens of spretus origin can mediate negative selection of T cells expressing transgenic TCR. The identification of these self antigens and the mechanism of thymic deletion and peripheral tolerance are under study in this model system.